ABSTRACT Exposures to environmental lead and cadmium can generate reactive oxygen species and have been linked to hearing impairment in high-risk communities. Because sensory receptor cells in the inner ear cannot regenerate, oxidative stress-induced damage to these cells is permanent, and consequent hearing loss persists throughout life. Even low levels of toxicants?when they co-occur with other risk factors, whether environmental or genetic?can cause significant impairment. However, the complex interactions between exposure to environmental ototoxicants and genetic susceptibility to hearing impairment are poorly understood. The long-term objective of my work is to understand gene- environment interactions in hearing impairment in high-risk communities, potentially providing a scientific basis for future environmental health policies. Firefighters are a high-risk population who are often co- exposed to multiple environmental risk factors. The proposed study will investigate the independent and interactive effects of environmental exposures and genetic risks on hearing impairment. Specifically, I hypothesize that distinct polymorphisms of SOD2 enhances the risk of hearing impairment associated with lead and cadmium exposure. The Specific Aims are to 1) determine the association between lead and cadmium exposure and hearing impairment in firefighters and 2) evaluate the interaction among SNPs of SOD2, lead and cadmium exposure, and hearing impairment. Audiograms will be used to assess hearing impairment. Bone lead levels will be analyzed by K-X-ray fluorescence imaging and urinary cadmium levels will be analyzed by ICP-mass spectrometry. Questionnaires and firefighter service records will be used to determine prior exposures to risk factors that are known to contribute to hearing impairment and that could confound the associations under study. Salivary DNA will be used to determine the distribution of 2 SNPs of SOD2 that are known to be associated with acquired hearing loss. Hearing impairment will be operationalized for analysis as a continuous measure representing the hearing thresholds. By identifying the combined influence of genetic and environmental risk factors, this study will facilitate the design of targeted hearing conservation programs that minimize co-exposure to potentiating environmental toxicants, which in turn could significantly decrease the incidence of hearing loss in high-risk communities. Further, the successful completion of the proposed research will enable the principal investigator of this TIEHR-K01 award, Dr. Samson Jamesdaniel, to develop greater competence 1) in designing and implementing research programs involving high-risk populations in vulnerable communities, 2) as a collaborator in epidemiologic studies, and 3) in employing multidisciplinary approaches to address important research questions. These efforts will help to establish the PI as an independent investigator of environmental health issues affecting urban populations.